1. Field of the Invention
The invention relates to a method for the preparation of lower alkyl esters of N-L-.alpha.-aspartyl-L-phenylalanine.
2. Description of the Prior Art
Lower alkyl esters of N-L-.alpha.-aspartyl-L-phenylalanine, especially the N-L-.alpha.-aspartyl-L-phenylalanine-1-methyl ester, which is called .alpha.-aspartame, are sought after as low calorie, well tolerated sweeteners.
Numerous processes for the preparation of .alpha.-aspartame and its homologous esters are described in the literature. These are either very complicated and therefore unsuitable for use on an industrial scale, or they are not specific and lead to a mixture of .alpha.- and .beta.-aspartame.
According to most of the known processes for the preparation of .alpha.-aspartame and its homologs, L-aspartyl anhydride, either protected at the nitrogen atom or unprotected, is reacted with the desired L-phenylalanine alkyl ester approximately as shown below: ##STR2##
After the protective group Z is split off, a mixture .alpha.- and .beta.-form of the product is obtained.
Attempts to influence the mixture ratio in favor of .alpha.-aspartame by suitable reaction conditions have met with only moderate success. Since only the .alpha.-form can be used as a sweetener, the economics of the manufacturing process become dramatically worse if the formation of the .beta.-form is not suppressed.
Methods for the preparation of selective .alpha.-aspartame and its homologous esters start out from the known L-aspartic acid N-carboxylic acid anhydride ##STR3##
As the reaction outlined above clearly shows, this leads selectively to .alpha.-aspartame. The instability of the anhydride mentioned however has made the industrial application of this theoretically simple process impossible until now.
A further selective method was described by Davey, et al, J. Chem. Soc. (Org) 1966(5), 555-66. According to this method, .alpha.-trichlorophenyl-.beta.-benzyl-N-benzyloxycarbonyl-L-aspartate is reacted with an L-phenylalanine ester and the product obtained is subsequently split hydrogenolytically. A similar synthesis, based on .alpha.-p-nitrophenyl-.beta.-benzyl-N-benzyloxycarbonyl-L-aspartate is described in French Pat. No. 1,577,545. The crucial disadvantage of the two last mentioned methods is the high cost of producing the N-carbobenzoxy-protected asymmetric diester of L-aspartic acid. Various authors have described the reaction of .beta.-benzyl-N-benzyloxycarbonyl-L-aspartic acid with L-phenylalanine methyl ester in the presence of N,N'-dicyclohexylcarbodiimide as a condensation agent. This leads selectively to .beta.-benzyl-N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine ester. However, this method is not suitable for industrial production since the starting material as well as the condensation agent is too expensive.
Recently, Vinick et al, Tetrahedron Letters 23 (13), 1315-19 (1982) and U.S. Pat. No. 4,256,897 described a selective process which is based on the use of L-aspartic acid N-thiocarboxy anhydride as an intermediate. This process is disadvantageous because it is accompanied by strong odors and therefore is not very suitable for the preparation of a food additive.
Consequently, there still is a considerable need for an economic, selective process for the preparation of .alpha.-aspartame and its homologous esters.